Hélène Jeltsch

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet the molecular mechanisms underlying hippocampal dysfunction remain poorly understood. To address this, we performed bulk RNA sequencing on hippocampal tissue from 17-week-old female MRL/Lpr mice and MRL^+/+ controls, followed by an integrative multi-layered analytical workflow. Differential gene expression analysis identified 223 significant differentially expressed genes, with a predominant downregulation of myelin-related transcripts. Gene set enrichment analysis confirmed coordinated suppression of oligodendrocyte differentiation, neuron ensheathment, and Wnt signaling programs. Weighted gene co-expression network analysis identified a disease-associated module enriched in myelination and glial developmental pathways, with hub genes spanning structural, transcriptional, and adhesion-related functions. Cell-type deconvolution revealed a selective reduction in mature oligodendrocytes, while oligodendrocyte precursor cells remained largely unaffected, consistent with impaired lineage maturation rather than global loss. RT-qPCR and Western blot validated the repression of key myelin-related genes and MBP protein in MRL/Lpr hippocampi. Collectively, these findings challenge an inflammation-centric interpretation of NPSLE hippocampal pathology, highlighting instead an additional contribution of impaired oligodendrocyte maturation. This transcriptomic resource establishes a molecular foundation for future mechanistic and histological investigations.

Objective: Neuropsychiatric systemic lupus erythematosus (NPSLE) is among the most challenging manifestations of systemic lupus erythematosus (SLE), affecting the central and peripheral nervous systems with diverse symptoms. Despite its prevalence, the diagnosis and management of NPSLE remain complex due to the heterogeneity of clinical presentations and the lack of specific biomarkers. This study aims to synthesize data from case reports to better understand the clinical, biological, and imaging features of NPSLE. Methods: A systematic review with integrated descriptive and exploratory quantitative analyses of 120 published case reports was conducted, integrating demographic, clinical, biological, and imaging data, as well as therapeutic approaches. Subgroup analyses stratified by age and sex were performed to identify descriptive patterns of presentation and outcomes. Results: Age- and sex-related patterns were observed in disease presentations. Patients presenting at younger ages more frequently exhibited renal and cutaneous involvement, whereas those presenting in adulthood or at older ages more often displayed neurological and neuropsychiatric manifestations, including motor dysfunction, cognitive impairment, and mood disorders. Male patients exhibited higher rates of severe renal involvement, whereas neuropsychiatric symptoms were more frequently reported, particularly among female cases. Neuroimaging abnormalities were identified in over 80% of patients in whom imaging was performed, with common findings including white matter lesions, cortical atrophy, and focal gray matter involvement. Despite the widespread use of corticosteroids and immunosuppressants, treatment gaps persisted, particularly in the management of neuropsychiatric symptoms. Conclusion: This review highlights the need for the development of biomarker-driven diagnostic tools and targeted therapies to address the unmet needs of NPSLE patients, while advances in imaging and biologics hold promises for improving patient outcomes. These findings should be interpreted as hypothesis-generating, given the descriptive nature of case-report–based evidence.

Introduction: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major clinical challenge, characterized by heterogeneous manifestations and the absence of reliable biomarkers. The mechanisms linking systemic autoimmunity to neuronal injury and neuropsychiatric symptoms remain poorly understood. Methods: Using the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mRNA mapping, cortical metabolomics, and behavioral analyses to dissect immune–metabolic–neuronal interactions. Results: Inflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as a prominent component of the inflammatory profile. Composite cytokine scores correlated strongly with plasma NfL, establishing an immune–neuronal injury axis. Region-resolved analyses revealed distinct CNS cytokine signatures, including selective hippocampal loss of interleukin-10 and IFNγ-dominated responses in the frontal cortex. Cortical metabolomics demonstrated diversion of tryptophan metabolism away from serotonin toward the kynurenine pathway, with increased quinolinic acid/kynurenic acid (QA/KA) ratio and upregulation of indoleamine 2,3-dioxygenase-1 ( Ido1 ) and kynurenine 3-monooxygenase ( Kmo ). NfL levels were negatively associated with serotonin and positively with 3-hydroxykynurenine and QA/KA, linking axonal damage to an excitotoxic metabolic environment. Importantly, cortical serotonin levels correlated with exploratory behavior, linking serotonergic depletion to anxiety-like phenotypes. Discussion: Together, these results support an associative framework in which systemic IFNγ levels are linked to cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood-based monitoring of IFNγ, NfL, and kynurenine metabolites may represent a candidate biomarker framework for NPSLE. However, validation in independent patient cohorts will be essential, and therapeutic modulation of IDO1/KMO or serotonergic pathways remains an avenue for future investigation.

Systemic lupus erythematosus (SLE) displays marked clinical and biological heterogeneity that is incompletely captured by group-based analyses. Although the MRL/Lpr mouse is a well-established lupus model, individual-level divergence within this genetically homogeneous strain remains poorly characterized. Here, we describe an MRL/Lpr mouse exhibiting an exceptionally severe systemic phenotype and provide an integrative characterization combining clinical assessment, inflammatory profiling, neuroaxonal injury, and targeted metabolomics. Despite pronounced clinical deterioration, including severe proteinuria, reduced organ weights, and marked neuroaxonal damage, this mouse did not show a globally exacerbated cytokine profile relative to other MRL/Lpr animals. In contrast, plasma neurofilament light chain levels were massively elevated, indicating substantial neuroaxonal injury. Targeted metabolomic analysis revealed a profoundly altered biochemical signature, with coordinated disruptions in nitrogen handling, sulfur amino acid metabolism, and neurometabolic pathways, clearly separating this animal from both control and lupus-prone peers.

Introduction: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major clinical challenge, characterized by heterogeneous manifestations and the absence of reliable biomarkers. The mechanisms linking systemic autoimmunity to neuronal injury and neuropsychiatric symptoms remain poorly understood. Methods: Using the lupus-prone MRL/Lpr mouse model, we integrated systemic cytokine profiling, plasma neurofilament light chain (NfL), region-specific CNS cytokine mapping, cortical metabolomics, and behavioral analyses to dissect immune–metabolic–neuronal interactions. Results: Inflammation was dominated by a Th1 cytokine program, with interferon-gamma emerging as the central driver. Composite cytokine scores correlated strongly with plasma NfL, establishing an immune–neuronal injury axis. Region-resolved analyses revealed distinct CNS cytokine signatures, including selective hippocampal loss of interleukin-10 and IFNγ-dominated responses in the frontal cortex. Cortical metabolomics demonstrated diversion of tryptophan metabolism away from serotonin toward the kynurenine pathway, with increased quinolinic acid/kynurenic acid (QA/KA) ratio and upregulation of indoleamine 2,3-dioxygenase-1 ( Ido1 ) and kynurenine 3-monooxygenase ( Kmo ). NfL levels were negatively associated with serotonin and positively with 3-hydroxykynurenine and QA/KA, linking axonal damage to an excitotoxic metabolic environment. Importantly, cortical serotonin levels correlated with exploratory behavior, linking serotonergic depletion to anxiety-like phenotypes. Discussion: Together, these results delineate a cascade in which systemic IFNγ is associated with cortical metabolic reprogramming and neuronal vulnerability, bridging peripheral immune activation with serotonergic depletion, melatonin loss, axonal injury, and behavioral dysfunction. Translationally, combined blood or CSF monitoring of IFNγ, NfL, and kynurenine metabolites could represent a candidate biomarker framework for NPSLE. However, validation in independent patient cohorts will be essential, and therapeutic modulation of IDO1/KMO or serotonergic pathways remains an avenue for future investigation.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet its hippocampal molecular underpinnings remain poorly understood. Here, we provide a region-specific transcriptomic map of the hippocampus in MRL/Lpr mice —a validated NPSLE model— compared to MRL ^+/+ controls. Bulk RNA-seq combined with integrative analyses ( e.g. differential expression, GSEA, WGCNA, cell-type deconvolution) uncovered a robust disease-specific signature centered on oligodendrocyte dysfunction and myelination failure. Key myelin-related genes ( Mbp , Plp1 , Mog ) and lineage-defining transcription factors ( Sox10 , Nkx6-2 , Olig2 ) were repressed, while OPC markers remained unchanged, indicating a maturation blockade rather than lineage loss. Gene set enrichment highlighted widespread suppression of oligodendrocyte differentiation, axon ensheathment, and Wnt/retinoic acid signaling, alongside dysregulation of extracellular matrix components critical for axo-glial interactions. Co-expression network analysis revealed a disease-associated module enriched in myelination programs, with hub genes spanning structural, transcriptional, and adhesion-related functions. Deconvolution analysis confirmed a selective reduction of mature oligodendrocytes, contrasting with preserved neuronal populations and absence of classical astroglial or microglial activation signatures. RT-qPCR and Western blot validated the repression of myelination pathways at both mRNA and protein levels. Collectively, these findings challenge the inflammation-centric paradigm of NPSLE, revealing a cell-intrinsic vulnerability of the oligodendrocyte lineage. This conceptual shift — from immune-driven damage to impaired glial development— redefines NPSLE pathogenesis and suggests novel therapeutic avenues targeting oligodendrocyte maturation and remyelination rather than focusing solely on immunosuppression.

Alzheimer’s disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals’ accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.

It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood–brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques.